Project Summary Cocaine abuse remains a significant public health problem for which there are no widely useful pharmacotherapies. Many preclinical leads have been generated that have not translated into successful medications for cocaine dependence. One reason for this failure may be that, although up to 90% of cocaine abusers also abuse alcohol, the medications development process (both preclinical animal experiments and early clinical testing of putative medications) has taken place in subjects with no exposure to alcohol. What little data that exists regarding cocaine/ethanol interactions suggests that this may represent a significant confound; ethanol can enhance some effects of cocaine in animals and humans and attenuate others. Moreover, recent clinical trials have shown that a history of alcohol dependence can reduce the ability of medications to decrease cocaine use. The proposed studies are designed to determine how long-term ethanol drinking alters the abuse-related effects of cocaine and vice versa in nonhuman primate models. First, we will determine whether prior ethanol exposure alters acquisition and maintenance (6 months) of cocaine self- administration. Parallel brain imaging studies using positron emission tomography (PET) will characterize how self-administration of ethanol, cocaine or the combination changes the availability of brain D2-like and D3 dopamine receptors, which have been implicated in both cocaine and ethanol abuse and have been suggested as targets for pharmacotherapy development. We will then examine whether these brain imaging measures correlate with the ability of potential pharmacotherapies to decrease cocaine use. Significant relationships would indicate that such measures could be used by physicians as biomarkers for behavioral phenotypes and for treatment effectiveness. Finally, the effects of self-administered cocaine on subsequent ethanol self- administration will be determined. Taken together, these studies will provide novel translatable data describing the effects of ethanol and cocaine on each other's abuse-related effects and, by characterizing precisely how combined use of these drugs alters DA receptors, will provide novel information to help guide treatment decisions for the large majority of cocaine users who concurrently abuse alcohol.